Unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer (solid tumors). (Folkman, Nature Med., 1, 27-31 (1995)). Because tumors require a blood supply to survive, angiogenesis is a critical component contributing to the cancer disease process (E. Ruoslahti, Nature Rev. Cancer, 2, 83-90 (2002). The development of new agents for the inhibition of angiogenesis therefore represents a promising approach for cancer therapy (R. Kerbel and J. Folkman, Nature Rev. Cancer, 2, 727-739 (2002). Another possible benefit to inhibiting tumor angiogenesis is that this approach may lack the toxic side effects or drug resistance-inducing properties of conventional chemotherapy (Judah Folkman, Endogenous Inhibitors of Angiogenesis, The Harvey Lectures, Series 92, pages 65-82, Wiley-Liss Inc., (1998)).
One of the protein kinases which has been shown to be involved in the angiogenic process is a member of the growth factor receptor tyrosine kinase family called VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor)). VEGF-R2, which is expressed primarily on endothelial cells, binds the potent angiogenic growth factor VEGF and mediates the subsequent signal transduction through activation of its intracellular kinase activity. Thus, it is expected that direct inhibition of the kinase activity of VEGF-R2 will result in the reduction of angiogenesis even in the presence of exogenous VEGF (see Strawn et al., Cancer Research, 56, 3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which fail to mediate signal transduction. (Millauer et al., Cancer Research, 56, 1615-1620 (1996)). The importance of VEGF-R2 as a target for cancer drug therapy was further indicated in recent studies (S. Rafii et al., Nature Rev. Cancer, 2, 826-835 (2002) and Y. Shaked et al., Cancer Cell, 7, 101-111 (2004)) which demonstrated that VEGF-R2 is expressed on bone marrow-derived circulating endothelial precursor cells that can also contribute to the angiogenesis and growth of tumors. Furthermore, VEGF-R2 appears to have no function in the adult beyond that of mediating the angiogenic activity of VEGF.
It has been proposed to treat angiogenesis by the use of compounds inhibiting the kinase activity of VEGF-R2. For example, WIPO International Publication No. WO 97/34876 discloses certain cinnoline derivatives that are inhibitors of VEGF-R2, which are taught to be useful for the treatment of disease states associated with abnormal angiogenesis and/or increased vascular permeability including diabetes (hyperglycemia), psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restinosis, autoimmune diseases, acute inflammation, ocular diseases with retinal vessel proliferation, and cancer.
Further, WO 03/092595 provides certain imidazo[1,2-a]pyridinyl compounds that inhibit, regulate, and/or modulate tyrosine kinase signal transduction.
There is still a need, however, for effective inhibitors of protein kinases.
The present invention provides novel imidazo[1,2-a]pyridinyl compounds that inhibit VEGF-R2 and are therefore useful in the treatment of VEGF-R2 mediated or dependent diseases such as the treatment of various forms of cancer.